1. Field of the Invention
The present invention relates to 5-methoxytryptophan and its derivatives and uses thereof. More specifically, the present invention relates to novel 5-methoxytryptophan and its derivatives and uses thereof for treating inflammatory-related diseases and cancers.
2. Description of Related Art
Abnormal activation of innate immune system has been implicated in the development of inflammatory disorders such as septic shock, multiple organ failure and atherosclerosis. Toll-like receptors (TLRs) play a critical role in regulating immune response and maintaining immune homeostasis. Inappropriate activation of TLR signaling by pathogen components and endogenous harmful molecules is a major contributor to systemic inflammation such as sepsis. There is growing evidence that TLRs play a key role in mediating systemic responses to invading pathogens during systemic inflammation and sepsis. In particular, activation of TLR4 by LPS is thought to be an important trigger of inflammatory response in sepsis. In addition to LPS, TLR4 can also be activated by endogenous molecules such as high mobility group box 1 (HMGB1) as a late mediator of lethal sepsis, which in turn initiates a secondary immunostimulatory cascade. Systemic inflammatory response syndrome is induced most commonly by a systemic infection of gram-negative bacteria and the subsequent release of LPS, which activates TLR4 signaling. The excessive stimulation of the host immune system by LPS results in high levels of inflammatory cytokines in the circulation and disseminated intravascular coagulation.
Systemic inflammation is characterized by metabolic syndrome, cardiovascular decompensation, multiple organ failure, disseminated intravascular coagulation and shock. These clinical manifestations are attributed to inappropriate or extensive inflammatory responses to uncontained bacterial infection and the endotoxins produced by gram-negative bacteria notably lipopolysaccharide (LPS). Excessive immune responses lead to production of very high levels of proinflammatory cytokines (cytokine storm) and overexpression of proinflammatory mediators such as cyclooxygenese-2 (COX-2) and inducible nitric oxide synthase (iNOS). Treatment of systemic inflammatory response syndrome is limited to fluid administration, oxygen supplement, antibiotics and other supportive measures. Specific therapeutic approaches targeting proinflammatory cytokines, coagulation cascade, LPS or immune responses are unsuccessful or have marginal efficacy.
Abnormal activation of the innate immune system and the resulting chronic inflammation have been implicated in the development and progression of chronic and metabolic diseases including atherosclerosis (Hansson G K & Hermansson A. The immune system in atherosclerosis. Nat Immunol 12:204-212 (2011)). Considerable evidence suggests that infectious agents could contribute to cardiovascular diseases. Vascular injury are often caused by uncontrolled infection with releases of endotoxins notably LPS. LPS activates toll-like receptor 4 (TLR4) which transmits signals to activate NF- B and C/EBP resulting in excessive production of proinflammatory mediators thereby inducing endothelial and vascular damages. In addition to LPS, TLR4 can also be activated by endogenous molecules such as high mobility group box 1 (HMGB1) as a late mediator of inflammation, which contributes to the development of atherosclerosis. ApoE-knockout mouse challenged with Porphyromonas gingivalis not only accelerates atherosclerosis but also increases expression of TLR2 and TLR4. Vascular disease is recognized as an inflammatory disease—inflammation activates endothelium and the underlying medial VSMCs (Hansson G K. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352, 1685-95 (2005)). The pathogenic VSMC migration and proliferation (leading to arteriosclerosis) are somewhat similar to that of systemic inflammation as well as cancer cell growth and invasion. We hypothesized that 5-MTP might protect against vascular injury-induced inflammation and the subsequent endothelial dysfunction and VSMC proliferation and migration, and consequent neointima formation.
Therefore, it is desirable to provide a new therapeutic agents and methods to conquer the aforementioned serious human illness.